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Heterocyclic compound

Active Publication Date: 2018-03-22
TAKEDA PHARMACEUTICALS CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

The present invention provides a compound with strong inhibitory action against MAGL, which can be used to prevent or treat neurodegenerative diseases such as Alzheimer's, Parkinson's disease, and Huntington's disease, as well as anxiety disorder, pain (both inflammatory and cancerous), epilepsy, and depression.

Problems solved by technology

However, when a cyclooxygenase inhibitor is used for a long time, digestive tract disorders are sometimes developed as side effects, thus posing a problem.
In addition, cardiovascular side effects such as myocardial infarction, cerebral infarction and the like also pose problems in recent years.
Traumatic brain injury (TBI) is a condition exerting an extremely harmful influence on the health of individuals, and an effective treatment method does not exist at present.
Glaucoma most often causes loss of eyesight, and is considered a serious social problem.

Method used

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  • Heterocyclic compound
  • Heterocyclic compound
  • Heterocyclic compound

Examples

Experimental program
Comparison scheme
Effect test

example 1

7-((4-(phenoxymethyl)piperidin-1-yl)carbonyl)-3,4-dihydroquinolin-2(1H)-one

[1181]To a mixture of 7-(4-(phenoxymethyl)piperidine-1-carbonyl)-3,4-dihydroquinolin-2(1H)-one (50.0 mg), 4-(phenoxymethyl)piperidine hydrochloride (40.0 mg) and DMF (1 mL) were added HATU (80.0 mg) and TEA (0.122 mL), and the mixture was stirred overnight at room temperature. The reaction mixture was diluted with ethyl acetate, water was added thereto, and the mixture was extracted with ethyl acetate. The organic layer was washed with water and saturated brine, dried over anhydrous sodium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane and methanol / ethyl acetate), and triturated with IPE / IPA to give the title compound (50.0 mg).

[1182]1H NMR (300 MHz, CDCl3) δ 1.19-1.52 (2H, m), 1.78-2.01 (2H, m), 2.03-2.21 (1H, m), 2.58-2.72 (2H, m), 2.77-2.93 (1H, m), 2.99 (3H, t, J=7.7 Hz), 3.72-4.05 (3H, m), 4.64-4.87 (1H, m), 6.78-7.07 (...

example 17

7-((4-((2,4-dichlorophenoxy)methyl)piperidin-1-yl)carbonyl)-1H-pyrido[2,3-b][1,4]oxazin-2 (3H)-one

A) 4-((2,4-dichlorophenoxy)methyl)piperidine hydrochloride

[1183]To a suspension of 60% sodium hydride (2.00 g) in DMF (25 mL) was added dropwise a solution of tert-butyl 4-(hydroxymethyl)piperidine-1-carboxylate (8.00 g) in DMF (25 mL) at 0° C., and then 2,4-dichloro-1-fluorobenzene (4.38 mL) was added thereto. The reaction mixture was stirred at room temperature for 18 hr. To the reaction mixture were added water and aqueous ammonium chloride solution, and the mixture was extracted with ethyl acetate. The organic layer was washed with saturated brine, dried over anhydrous magnesium sulfate, and concentrated under reduced pressure. The residue was purified by silica gel column chromatography (ethyl acetate / hexane) to give tert-butyl 4-((2,4-dichlorophenoxy)methyl)piperidine-1-carboxylate as a crude product.

[1184]To a solution of the obtained crude product in ethyl acetate (10 mL) was ad...

example 24

6-((4-((2-chlorophenoxy)methyl)piperidin-1-yl)carbonyl)-2H-1,4-benzoxazin-3 (4H)-one

[1188]A mixture of 4-((2-chlorophenoxy)methyl)piperidine hydrochloride (48.0 mg), 3-oxo-3,4-dihydro-2H-benzo[b][1,4]oxazine-6-carboxylic acid (50.0 mg), HOBt-H2O (47.6 mg), EDCI (59.5 mg), DIPEA (0.113 mL) and DMF (2 mL) was stirred at room temperature for 3 hr. To the reaction mixture was added water, and the resulting precipitate was collected, washed with water and ethyl acetate, dried under reduced pressure, and triturated with heated ethyl acetate to give the title compound (47.0 mg).

[1189]1H NMR (300 MHz, DMSO-d6) δ 1.19-1.40 (2H, m), 1.72-1.93 (2H, m), 2.01-2.17 (1H, m), 2.70-3.18 (2H, m), 3.49-4.52 (4H, m), 4.62 (2H, s), 6.89-7.02 (4H, m), 7.14 (1H, dd, J=8.3, 1.1 Hz), 7.25-7.34 (1H, m), 7.41 (1H, dd, J=7.9, 1.5 Hz), 10.80 (1H, s).

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Abstract

The present invention provides a compound having an MAGL inhibitory action, which is expected to be useful as an agent for the prophylaxis or treatment of neurodegenerative diseases (e.g., Alzheimer's disease, Parkinson's disease, Huntington's disease, amyotrophic lateral sclerosis, traumatic brain injury, glaucoma, multiple sclerosis etc.), anxiety disorder, pains (e.g., inflammatory pain, cancerous pain, neurogenic pain etc.), epilepsy, depression and the like.The present invention relates a compound represented by the formula (I):wherein each symbol is as described in the specification, or a salt thereof.

Description

TECHNICAL FIELD[0001]The present invention relates to a heterocyclic compound having a monoacylglycerol lipase (sometimes to be abbreviated as “MAGL” in the present specification) inhibitory action, a pharmaceutical composition containing same, and the like.BACKGROUND OF THE INVENTION[0002]Arachidonic acid (sometimes to be abbreviated as “AA” in the present specification), and eicosanoids, which are products in vivo, have been reported to cause inflammation in the central nervous system and peripheral [non-patent document 1: Science, vol. 294, pages 1871-1875, 2001]. An inhibitor that suppresses arachidonic acid production pathway, and eicosanoid production pathway is promising as a therapeutic drug for inflammatory diseases, and non-steroidal anti-inflammatory drugs such as cyclooxygenase inhibitor and the like have been used as therapeutic drugs for inflammatory pain. However, when a cyclooxygenase inhibitor is used for a long time, digestive tract disorders are sometimes develope...

Claims

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Application Information

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IPC IPC(8): C07D498/04C07D401/10C07D413/10C07D413/14C07D417/14
CPCC07D498/04C07D401/10C07D413/10C07D413/14C07D417/14A61P21/00A61P25/00A61P25/04A61P25/08A61P25/14A61P25/16A61P25/22A61P25/24A61P25/28A61P43/00A61K31/454A61K31/4709A61K31/538A61K31/5383C07D401/06C07D413/06C07D471/04C12N9/99
Inventor IKEDA, SHUHEIKOIKE, TATSUKIAIDA, JUMPEIFUSHIMI, MAKOTOKUSUMOTO, TOMOKAZUSUGIYAMA, HIDEYUKIMIYAZAKI, MASAKOTOKUHARA, HIDEKAZUHATTORI, YASUSHIKAMATA, MAKOTO
Owner TAKEDA PHARMACEUTICALS CO LTD
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